PXD052762

PXD052762 is an original dataset announced via ProteomeXchange.

Title	Identification of potent and reversible piperidine carboxamides that are species-selective orally active proteasome inhibitors to treat malaria
Description	Malaria remains a global health threat as drug resistance threatens treatment programs. We identified a piperidine carboxamide (SW042) with anti-malarial activity by phenotypic screening. Selection of SW042-resistant Plasmodium falciparum (Pf) parasites revealed point mutations in the Pf_proteasome 5 active-site. A potent analog (SW584) showed efficacy in a mouse model of human malaria after oral dosing. SW584 had a low propensity to generate resistance (Minimum Inoculum of Resistance >109) and was synergistic with dihydroartemisinin. Pf_proteasome purification was facilitated by His8-tag introduction onto 7. Inhibition of Pf5 correlated with parasite killing, without inhibiting the human proteasome or showing cytotoxicity. The Pf_proteasome_SW584 cryo-EM structure showed SW584 bound non-covalently distal from the catalytic threonine, in an unexplored pocket at the 5/6/3 subunit interface that shows species differences between Pf and human proteasomes. Identification of a reversible, species selective, orally active series with low resistance propensity, provides a path for drugging this essential target.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:51:53.188.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Andrew Lemoff
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606; scientific name: Plasmodium falciparum (isolate 3D7); NCBI TaxID: 36329;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2024-05-31 09:59:26	ID requested
1	2024-07-30 08:34:40	announced
⏵ 2	2024-10-22 06:51:53	announced	2024-10-22: Updated project metadata.

10.1016/J.CHEMBIOL.2024.07.001;

submitter keyword: Plasmodium, drug discovery, malaria, drug resistance, proteasome

Margaret A. Phillips
contact affiliation	Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, Texas 75390, USA
contact email	margaret.phillips@utsouthwestern.edu
lab head
Andrew Lemoff
contact affiliation	UT Southwestern Medical Center
contact email	andrew.lemoff@utsouthwestern.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2024/07/PXD052762

PRIDE project URI

• PRIDE
  1. PXD052762
     1. Label: PRIDE project
     2. Name: Identification of potent and reversible piperidine carboxamides that are species-selective orally active proteasome inhibitors to treat malaria